The present invention is based on the theory that an unexpected and surprising synergy will be found with a combination therapy involving opioid antagonists and selective serotonin reuptake inhibitors which has been neither disclosed nor suggested by the prior art. Such a therapy would provide a new and highly beneficial method for the treatment of alcohol dependence.
Disulfiram (Antabuse.RTM.) is the only FDh approved product that is currently available for adjunctive use in the treatment of alcohol abuse (T. W. Rall, in: Goodman and Gilman's The Pharmacological Basis of Therapeutics, A. G. Gilman et al., 8th Edition, Chap. 17, pp. 378-379, Pergamon Press, 1990). Disulfiram works by blocking the intermediary metabolism of alcohol. Most alcohol is normally metabolized to acetaldehyde which is further oxidized to innocuous byproducts which are excreted or recycled through energy-producing or other biosynthetic pathways. When alcohol is consumed in the presence of disulfiram, blood acetaldehyde concentrations increase to many-fold higher than normal values and produce markedly adverse behavioral and physiological responses that are collectively described as the "acetaldehyde syndrome." Psychological theory suggests that patients will avoid further consumption of alcohol to avoid these alarming and potentially life-threatening responses.
More recently, several investigators have reported that naltrexone is a useful adjunctive treatment following alcohol detoxification in alcohol-dependent human subjects (J. R. Volpicelli et al., Arch. Gen. Psychiatry, 49, 876, 1992; S. S. O'Malley et al. ibid., 49, 881, 1992). Naltrexone blocks alcohol craving and reduces total alcohol consumption without producing mood changes or psychiatric symptoms. The applicant suggests that naltrexone may be particularly useful in preventing alcohol relapse. Naltrexone, a well-known narcotic antagonist, is thought to work by blocking activation of the endogenous opioid reward system. Hence, naltrexone blocks the action of endorphins, enkephalins, and other endogenous opioids which may be released in response to alcohol consumption. Similar results have been obtained in studies in rats and monkeys where naltrexone, naloxone, nalmefene, and other opioid antagonists have been shown to block the apparent rewarding effects of alcohol and reduce total alcohol consumption (D. R. Brown and S. G. Holtzman, Pharmacol. Biochem. Behav., 11, 567, 1979; L. D. Reid and G. A. Hunter, Alcohol, 1, 33, 1984; C. L. Hubbell et al., Alcohol, 3, 39, 1986; R. D. Myers et al., Alcohol, 3, 383, 1986; C. L. Hubbell et al., Alcohol, 8, 355, 1991; D. V. Gauvin et al., Alcohol, 10, 37, 1993).
Medications that enhance brain serotonergic activity have also shown effectiveness in reducing alcohol consumption and are currently under evaluation for long-term treatment of alcoholism. For example, C. A. Naranjo et al., Clin. Pharm. Ther., 35, 374, 1984, and Clin. Pharm. Ther., 41, 266, 1987, have shown that the serotonin uptake inhibitors citalopram and zimeldine attenuate ethanol intake in nondepressed alcohol abusers. C. L. Hubbell et al., Alcohol, 8, 355, 1991, demonstrated that fluoxetine, another serotonin uptake inhibitor, attenuates alcohol intake in rats. In a review article, C. A. Naranjo et al., J. Clin. Psychiatry, 47, 16, 1986, indicate that several serotonin uptake inhibitors including zimelidine, citalopram, fluoxetine, and fluvoxamine decrease ethanol drinking in rats.
In the present invention, we claim an unexpected synergistic interaction between naltrexone, an opioid antagonist, and fluoxetine, a serotonin uptake inhibitor, on alcohol fluid consumption in rats. The synergism may be demonstrated where small combined doses of naltrexone and fluoxetine which are inactive by themselves are as effective as much higher doses of either drug alone. Alternatively, the data may show that the observed median effective doses (ED50 responses) for various fixed dose combinations of naltrexone and fluoxetine are significantly lower than can be accounted for by a simple additivity hypothesis. The data may show that the combination of a long-lasting opioid antagonist with a serotonin uptake inhibitor may provide a novel adjunctive treatment for alcohol abuse and alcoholism in man.